4-[4-(2-Pyrimidinyl)piperazino]butanenitrile -Drug Synthesis Database

【结构式】

【分子编号】11180

【品名】4-[4-(2-Pyrimidinyl)piperazino]butanenitrile

【CA登记号】

【分子式】C₁₂H₁₇N₅

【分子量】231.30068

【元素组成】C 62.31% H 7.41% N 30.28%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

This compound has been obtained by two related ways: The reduction of 4-[4-(2-pyrimidinyl)piperazin-1-yl]butyronitrile (I) by means of RaNi and hydrazine in isopropanol gives 4-[4-(2-pyrimidinyl)piperazin-1-yl]butylamine (II), which is then condensed with 3,3-dimethylglutaric anhydride (III) in refluxing xylene or refluxing toluene to yield the target glutarimide derivative. Alternatively, the condensation of N-(4-bromobutyl)-3,3-dimethylglutarimide (IV) with 1-(2-pyrimidinyl)piperazine (V) by means of K2CO3 in refluxing acetonitrile also yields the target glutarimide derivative.

参考文献中间体

合成目标

【1】 Yevich, J.P.; et al.; Buspirone analogues. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives. J Med Chem 1983, 26, 2, 194.
【2】 Temple, D.L. Jr. (Bristol-Myers Squibb Co.); 2-[4-[(4,4-Dialkyl-2,6-piperidinedion-1-yl)butyl]-1-piperazinyl]pyrimidines. BE 0895504; CH 656383; DE 3248160; FR 2518993; GB 2114122; JP 1983118582; JP 1994293753; US 4423049 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	11180	4-[4-(2-Pyrimidinyl)piperazino]butanenitrile		C₁₂H₁₇N₅	详情	详情
(II)	11181	4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine	33386-20-8	C₁₂H₂₁N₅	详情	详情
(III)	25549	4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione	4160-82-1	C₇H₁₀O₃	详情	详情
(IV)	56851	1-(4-bromobutyl)-4,4-dimethyl-2,6-piperidinedione		C₁₁H₁₈BrNO₂	详情	详情
(V)	11175	2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine	20980-22-7	C₈H₁₂N₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

New syntheses of tandospirone have been described: 1) The hydrogenation of bicyclo[2.2.1]hept-5-ene-2,3-di-exo-carboxylic acid anhydride (I) with H2 over Pd/C in THF-water gives bicyclo[2.2.1]heptane-2,3-di-exo-carboxylic acid anhydride (II), which by reaction with ammonia in THF-water is converted into the imide (III). The reaction of (III) with 1,4-dibromobutane by means of K2CO3 in refluxing acetone yields N-(4-bromobutyl)bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (IV), which is finally condensed with 1-(2-pyrimidinyl)piperazine (V) by means of K2CO3 and KI in hot DMF. 2) Imide (III) is condensed with propargyl bromide (VI) by means of K2CO3 in refluxing acetone affording N-propargylbicyclo[2.2.1]heptane-2,3-di-exo-carboximide (VII), which is allowed to react with piperazine (V) and formaldehyde by means of CuSO4 in dioxane to give N-[4-[4-(2-pyrimidinyl)piperazin-1-yl]-2-butynyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (VIII). Finally, this compound is reduced with H2 over Pd/C. 3) The condensation of piperazine (V) with 4-chlorobutyronitrile (IX) by means of NaOH in acetone gives 4-[4-(2-pyrimidinyl)piperazin-1-yl]butyronitrile (X), which is reduced with LiAlH4 in ether yielding 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (XI). Finally, this compound is condensed with anhydride (II) in refluxing pyridine.

参考文献中间体

合成目标

【1】 Kojima, A.; Ishizumi, K.; Antoku, F.; Synthesis and anxiolytic activity of N-substituted cyclic imides (1R,2S,3R,4S)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3-bicyclo[2.2.1]heptanedicarboximide (tandospirone) and related compounds. Chem Pharm Bull 1991, 39, 9, 2288.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	11171	(1R,2R,6S,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione		C₉H₈O₃	详情	详情
(II)	11172	(1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]decane-3,5-dione	6004-79-1	C₉H₁₀O₃	详情	详情
(III)	11173	(1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione		C₉H₁₁NO₂	详情	详情
(IV)	11174	(1R,2S,6R,7S)-4-(4-Bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione		C₁₃H₁₈BrNO₂	详情	详情
(V)	11175	2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine	20980-22-7	C₈H₁₂N₄	详情	详情
(VI)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(VII)	11177	(1R,2S,6R,7S)-4-(2-Propynyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione		C₁₂H₁₃NO₂	详情	详情
(VIII)	11178	(1R,2S,6R,7S)-4-[4-[4-(2-Pyrimidinyl)piperazino]-2-butynyl]-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione		C₂₁H₂₅N₅O₂	详情	详情
(IX)	11179	4-Chlorobutanenitrile; 4-Chlorobutyronitrile	628-20-6	C₄H₆ClN	详情	详情
(X)	11180	4-[4-(2-Pyrimidinyl)piperazino]butanenitrile		C₁₂H₁₇N₅	详情	详情
(XI)	11181	4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine	33386-20-8	C₁₂H₂₁N₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

The condensation of 1-(2-pyrimidinyl)piperazine (I) with 3-chloro-1-cyanopropane (II) by means of Na2CO3 in n-butanol gives 4-(2-pyrimidinyl)-1-(3-cyanopropyl)piperazine (III). This product is reduced with LiAlH4 or with H2 and Raney-Ni yielding 4-(2-pyrimidinyl)-1-(4-aminobutyl)piperazine (IV), which is finally condensed with 8-oxaspiro[4.5]decane-7,9-dione-(3,3-tetramethylene-glutaric anhydride) (V) in pyridine.

参考文献中间体

合成目标

【1】 Wu, Y.H.; et al.; N-(Heteroarcyclic)piperazizylalkylazaspiroalkanediones. DE 2057845; FR 2073406; GB 1332194; US 3717634 .
【2】 Wu, Y.H.; et al.; Psychosedative agents. 2. 8-(4-substituted-1-piperazinylalkyl)-8-azaspiro-[4,5]decane-7,9-diones. J Med Chem 1972, 15, 5, 477-479.
【3】 Castaner, J.; Thorpe, P.; Buspirone. Drugs Fut 1976, 1, 9, 409.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	11175	2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine	20980-22-7	C₈H₁₂N₄	详情	详情
(II)	11179	4-Chlorobutanenitrile; 4-Chlorobutyronitrile	628-20-6	C₄H₆ClN	详情	详情
(III)	11180	4-[4-(2-Pyrimidinyl)piperazino]butanenitrile		C₁₂H₁₇N₅	详情	详情
(IV)	11181	4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine	33386-20-8	C₁₂H₂₁N₅	详情	详情
(V)	34125	8-oxaspiro[4.5]decane-7,9-dione	5662-95-3	C₉H₁₂O₃	详情	详情

Extended Information